The invention relater to a composite laminate, in particular a transdermal therapeutic system (TTS), which comprises in at least one layer a moisture sensitive active substance and possesses a further layer, spatially separate from this active substance layer, which is capable of absorbing moisture, and to a process for producing such a composite laminate.
The transdermal administration of pharmaceutical active substances has been known from the time of the first commercial utilization of a scopolamine transdermal therapeutic system (Scopoderm TTS). Other active substances (nitroglycerine, estradiol, clonidine, isosorbide dinitrate, fentanyl, nicotine, norethisterone, etc.) have since been offered in the form of such a TTS. The layer-constructed active substance patches are adhered to the skin of a patient. The active substance can then be released from the TTS to the skin of the patient in a controlled manner.
Various types of such TTS have been described, for example, by Y. W. Chien in xe2x80x9cDevelopmental Concepts and Practice in Transdermal Therapeutic Systemsxe2x80x9d, in Transdermal Controlled Systemic Medications, ed. by Y. W. Chien, Marcel Dekker, Inc., New York (1982), Chapter 2, pp. 25-81. Accordingly, essential elements of a TTS are the active substance impermeable backing layer, an active substance reservoir or matrix layer, an optional semipermeable or microporous membrane to control the release of the active substance from the reservoir, an optional pressure sensitive adhesive layer, and an abhesive protective layer (release liner) which is removed from the pressure sensitive adhesive, skin contact side of the TTS before the TTS is used. In order to avoid repetition, the content of said chapterxe2x80x94especially the TTS types described thereinxe2x80x94is hereby incorporated by reference as part of the disclosure of the present description. Owing to its layer construction, therefore, a TTS is a composite laminate, i.e., a device constructed of at least two layers.
One problem which may occur during the production and storage of TTS derives from the sensitivity of individual components, especially certain active substances, to moisture. This means that exposure even to small amounts of water may be accompanied by a physical and/or chemical transformation of the component and/or active substance, a consequence of which is that said component may lose its structural integrity or that the full activity of said active substance is no longer available for the pharmaceutical application.
Examples of substances, especially pharmaceutical active substances, which may suffer the abovementioned transformations on exposure to moisture are acetylsalicylic acid (ASA) and 17xcex2-estradiol. In the case of acetylsalicylic acid there is a chemical reaction (hydrolysis), forming salicylic acid and acetic acid. In the case of 17xcex2-estradiol there is a physical transformation (crystallization), forming hydrated crystals of poor solubility. As a consequence of these transformations, the pharmaceutical active substance is present dissolved in a reduced concentration in the various layers of the TTS, especially the matrix layer, the reservoir, and/or the pressure sensitive adhesive layer. In general, however, the desire is for a high concentration of dissolved active substance in the various layers of the TTS, especially the skin contact layer, in order to ensure a sufficiently large concentration difference between skin contact layer and the skin of the patient throughout the period of application of the TTS. It is this concentration difference, in fact, which is the driving force for the diffusion of the active substance into the skin and the blood circulation.
In order to prevent the problem of crystallization of the active substance owing to moisture exposure, various methods and means have been developed in order to reduce the culprit moisture content in the TTS-containing devicexe2x80x94which in this case is the primary packaging, usually a sealed pouch.
Thus in DE 42 37 453 it has been proposed to produce and store the transdermal therapeutic systems comprising the moisture sensitive active substance 17xcex2-estradiol under conditions of reduced atmospheric humidity. This was done by including a desiccant, in the form of several grains of blue gel, with the TTS in the sealed pouch.
DE 196 46 048 describes packaging for transdermal therapeutic systems which comprises an internally fixed drying device. The drying device is of flat construction and comprises a solid desiccant. Said drying devices are produced in a multistage process. In a first operation, the desiccant label must be produced by individualization from a desiccant laminate in web form; in a second operation it must be provided with an intermediate liner; and in a third operation, involving the removal of this abhesive intermediate liner, it must be positioned precisely on the web which produces the subsequent interior of the sealed pouch, and firmly and permanently bonded. In a further, separate operation, the TTS comprising the active substance in question must be produced. Finally, said TTS must be placed on the sealing pouch laminate web on which the individual desiccant labels have been bonded, and this web must be cut and sealed in such a way that the desiccant label does not lie on the resulting weld seams. The execution of these different operations and processes must be carried out in the absence of or with greatly reduced atmospheric humidity, which may additionally necessitate rapid working. Owing, however, to the required accuracy in the positioning of the desiccant label on the laminate, and in the positioning of the TTS on the laminate thus bonded, this is very technically demanding and/or very complex in terms of apparatus.
It is an object of the present invention to provide a device by means of which a composite laminate, especially a transdermal therapeutic system (TTS), which comprises in at least one layer a moisture-sensitive component, especially a moisture sensitive active substance, can be stored in a closed gas space under reduced atmospheric humidity, and a process for producing such a device. The intention is to provide devices with a simpler construction and processes which avoid the difficulties depicted in the production of the prior art devices.
This object is achieved in accordance with the present invention by means of a composite laminate comprising at least two different layers. The composite laminate of the invention comprises at least one moisture sensitive layer (1) which comprises a moisture sensitive component. The composite laminate of the invention further comprises a moisture absorbing layer (2) which is free from active substance and is capable of absorbing moisture. The two separate layers can be adjacent and in direct contact with one another; preference is given, however, to embodiments in which these two layers are spatially separate from one another. Said composite laminate may preferably comprise a transdermal therapeutic system comprising at least one moisture-sensitive active substance.